Electric modulation of sympathetic nervous system

ABSTRACT

A method is described for the treatment of obesity or other disorders, by electrical activation or inhibition of the sympathetic nervous system. This activation or inhibition can be accomplished by electrically stimulating the greater splanchnic nerve or other portion of the sympathetic nervous system using an implantable pulse generator. This nerve activation can result in reduced food intake and increased energy expenditure. Reduced food intake may occur through a variety of mechanisms that reduce appetite and cause satiety. Increased adrenal gland hormone levels will result in increased energy expenditure. Fat and carbohydrate metabolism, which are also increased by sympathetic nerve activation, will accompany the increased energy expenditure.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional U.S. application Ser. No. 11/804,449,filed May 17, 2007, pending, entitled “Electric Modulation ofSympathetic Nervous System,” which is a divisional of U.S. applicationSer. No. 10/243,612, filed Sep. 13, 2002, now U.S. Pat. No. 7,239,912,entitled “Electric Modulation of Sympathetic Nervous System,” whichclaims the benefit of U.S. Provisional Application No. 60/366,750, filedMar. 22, 2002, entitled “Sympathetic Nervous System ElectricalStimulation for Weight Control”; U.S. Provisional Application No.60/370,311, filed Apr. 5, 2002, entitled “Splanchnic Nerve Stimulationand Anchoring to the Crus of the Diaphragm for Obesity Treatment”; U.S.Provisional Application No. 60/379,605, filed May 10, 2002, entitled“Percutaneous Placement of an Electrode for Splanchnic Nerve StimulationWith and Without Thorascopic Visualization for Obesity and DiabetesTherapy”; U.S. Provisional Application No. 60/384,219, filed May 30,2002, entitled “Sympathetic Nervous System Electrical Stimulation forWeight Control”; and U.S. Provisional Application No. 60/386,699, filedJun. 10, 2002, entitled “Treatment of Obesity and Other MedicalConditions Through Electrical Nerve Modulation of the SympatheticNervous System,” the disclosures of which are hereby incorporated byreference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is in the field of nerve stimulation for the treatment ofmedical conditions.

2. Background Art

Obesity is considered an epidemic in the U.S. with a prevalence of19.8%. The annual healthcare costs associated with obesity are estimatedto exceed $200 BB. Obesity is defined as a body mass index (BMI) thatexceeds 30 kg/m2. Normal BMI is 18.5-25 kg/m2 and overweight personshave BMIs of 25-30. Obesity is classified into three groups moderate(Class 1), severe (Class II), and very severe (Class Patients with BMIsthat exceed 30 are at risk for significant comorbidities such asdiabetes, heart and kidney disease, dyslipidemia, hypertension, sleepapnea, and orthopedic problems.

Obesity results from an imbalance between food intake and energyexpenditure such that there is a net increase in fat reserves. Excessivefood intake, reduced energy expenditure, or both may cause thisimbalance. Appetite and satiety, which control food intake, are partlycontrolled in the brain by the hypothalamus. Energy expenditure is alsopartly controlled by the hypothalamus. The hypothalamus regulates theautonomic nervous system of which there are two branches, thesympathetic and the parasympathetic. The sympathetic nervous systemgenerally prepares the body for action by increasing heart rate, bloodpressure, and metabolism. The parasympathetic system prepares the bodyfor rest by lowering heart rate, lowering blood pressure, andstimulating digestion. Destruction of the lateral hypothalamus resultsin hunger suppression, reduced food intake, weight loss, and increasedsympathetic activity. In contrast, destruction of the ventromedialnucleus of the hypothalamus results in suppression of satiety, excessivefood intake, weight gain, and decreased sympathetic activity. Thesplanchnic nerves carry sympathetic neurons that supply, or innervate,the organs of digestion and adrenal glands, and the vagus nerve carriesparasympathetic neurons that innervate the digestive system and areinvolved in the feeding and weight gain response to hypothalamicdestruction.

Experimental and observational evidence suggests that there is areciprocal relationship between food intake and sympathetic nervoussystem activity. Increased sympathetic activity reduces food intake andreduced sympathetic activity increases food intake. Certain peptides(e.g. neuropeptide Y, galanin) are known to increase food intake whiledecreasing sympathetic activity. Others such as cholecystokinin, leptin,enterostatin, reduce food intake and increase sympathetic activity. Inaddition, drugs such as nicotine, ephedrine, caffeine, subitramine,dexfenfluramine, increase sympathetic activity and reduce food intake.

Ghrelin is another peptide that is secreted by the stomach that isassociated with hunger. Peak plasma levels occur just prior to mealtime, and ghrelin levels are increased after weight loss. Sympatheticactivity may suppress ghrelin secretion.

Appetite is stimulated by various psychosocial factors, but is alsostimulated by low blood glucose levels. Cells in the hypothalamus thatare sensitive to glucose levels are thought to play a role in hungerstimulation. Sympathetic activity increases plasma glucose levels.Satiety is promoted by distension of the stomach and delayed gastricemptying. Sympathetic activity reduces duodenal motility and increasespyloric sphincter, which may result in distention and delayed gastricemptying.

The sympathetic nervous system plays a role in energy expenditure andobesity. Genetically inherited obesity in rodents is characterized bydecreased sympathetic activity to adipose tissue and other peripheralorgans. Catecholamines and cortisol, which are released by thesympathetic nervous system, cause a dose-dependent increase in restingenergy expenditure. In humans, there is a reported negative correlationbetween body fat and plasma catecholamine levels. Overfeeding orunderfeeding lean human subjects has a significant effect on energyexpenditure and sympathetic nervous system activation. For example,weight loss in obese subjects is associated with a compensatory decreasein energy expenditure, which promotes the regain of previously lostweight. Drugs that activate the sympathetic nervous system, such asephedrine, caffeine and nicotine, are known to increase energyexpenditure. Smokers are known to have lower body fat stores andincreased energy expenditure.

The sympathetic nervous system also plays an important role inregulating energy substrates for increased expenditure, such as fat andcarbohydrate. Glycogen and fat metabolism are increased by sympatheticactivation and are needed to support increased energy expenditure.

Animal research involving acute electrical activation of the splanchnicnerves under general anesthesia causes a variety of physiologic changes.Electrical activation of a single splanchnic nerve in dogs and cowscauses a frequency dependent increase in catecholamine, dopamine, andcortisol secretion. Plasma levels can be achieved that cause increasedenergy expenditure. In adrenalectomized anesthetized pigs, cows, anddogs, acute single splanchnic nerve activation causes increased bloodglucose and reduction in glycogen liver stores. In dogs, singlesplanchnic nerve electrical activation causes increased pyloricsphincter tone and decrease duodenal motility. Sympathetic andsplanchnic nerve activation can cause suppression of insulin and leptinhormone secretion.

First line therapy for obesity is behavior modification involvingreduced food intake and increased exercise. However, these measuresoften fail and behavioral treatment is supplemented with pharmacologictreatment using the pharmacologic agents noted above to reduce appetiteand increase energy expenditure. Other pharmacologic agents that maycause these affects include dopamine and dopamine analogs, acetylcholineand cholinesterase inhibitors. Pharmacologic therapy is typicallydelivered orally and results in systemic side effects such astachycardia, sweating, and hypertension. In addition, tolerance candevelop such that the response to the drug reduces even at higher doses.

More radical forms of therapy involve surgery. In general, theseprocedures reduce the size of the stomach and/or reroute the intestinalsystem to avoid the stomach. Representative procedures are gastricbypass surgery and gastric banding. These procedures can be veryeffective in treating obesity, but they are highly invasive, requiresignificant lifestyle changes, and can have severe complications.

Experimental forms of treatment for obesity involve electricalstimulation of the stomach (gastric pacing) and the vagus nerve(parasympathetic system). These therapies use a pulse generator toelectrically stimulate the stomach or vagus nerve via implantedelectrodes. The intent of these therapies is to reduce food intakethrough the promotion of satiety and or reduction of appetite, andneither of these therapies is believed to affect energy expenditure.U.S. Pat. No. 5,423,872 to Cigaina describes a method for treatingeating disorders by electrically pacing the stomach. The believedmechanism of action is the promotion of satiety by reducing gastricactivity and consequently delaying stomach content emptying. Reductionof appetite may also occur, but this is unclear. U.S. Pat. No. 5,263,480to Wernicke discloses a method for treating obesity by electricallyactivating the vagus nerve. This therapy may promote satiety as afferentfibers that are stimulated by stomach distention are carried in thevagus nerve. Neither of these therapies increases energy expenditure.

BRIEF SUMMARY OF THE INVENTION

The present invention includes a method for treating obesity or otherdisorders by electrically activating the sympathetic nervous system.Obesity can be treated by activating the efferent sympathetic nervoussystem, thereby increasing energy expenditure and reducing food intake.Stimulation is accomplished using a pulse generator and electrodesimplanted near, or attached to, various areas of the sympathetic nervoussystem, such as the sympathetic chain ganglia, the splanchnic nerves(greater, lesser, least), or the peripheral ganglia (eg. celiac,mesenteric). Ideally, the obesity therapy will employ electricalactivation of the sympathetic nervous system that innervates thedigestive system, adrenals, and abdominal adipose tissue, such as thesplanchnic nerves or celiac ganglia.

This method of obesity treatment may reduce food intake by a variety ofmechanisms, including general increased sympathetic system activationand increasing plasma glucose levels upon activation. Satiety may beproduced through direct affects on the pylorus and duodenum that causestomach distension and delayed stomach emptying. In addition, foodintake may be reduced by reducing ghrelin secretion.

This method of obesity treatment may also increase energy expenditure bycausing catecholamine, cortisol, and dopamine release from the adrenalglands. The therapy could be titrated to the release of these hormones.Fat and carbohydrate metabolism, which are also increased by sympatheticnerve activation, will accompany the increased energy expenditure. Otherhormonal effects induced by this therapy may include reduced insulinsecretion. Alternatively, this method may be used to normalizecatecholamine levels, which are reduced with weight gain.

Electrical sympathetic activation for treating obesity is ideallyaccomplished without causing a rise in mean arterial blood pressure(MAP). This may be achieved by using an appropriate stimulation patternwith a relatively short signal-on time followed by an equal or longersignal-off time. During activation therapy, a sinusoidal-likefluctuation in the MAP may occur with an average MAP that is within safelimits. Alternatively, an alpha sympathetic receptor blocker, such asprazosin, could be used to blunt the increase in MAP.

Electrical sympathetic activation may be titrated to the plasma level ofcatecholamines achieved during therapy. This would allow the therapy tobe monitored and safe levels of increased energy expenditure to beachieved. The therapy could also be titrated to plasma ghrelin levels.

Electrical modulation (inhibition or activation) of the sympatheticnerves can also be used to treat other eating disorders such as anorexiaor bulimia. For example, inhibition of the sympathetic nerves may beuseful in treating anorexia. Electrical modulation of the sympatheticnerves may also be used to treat gastrointestinal diseases such aspeptic ulcers, esophageal reflux, gastroparesis, and irritable bowel.For example, stimulation of the splanchnic nerves that innervate thelarge intestine may reduce the symptoms of irritable bowel syndrome,characterized by diarrhea. Pain may also be treated by electric nervemodulation of the sympathetic nervous system, as certain pain neuronsare carried in the sympathetic nerves. This therapy may also be used totreat type II diabetes. These conditions may require varying degrees ofinhibition or stimulation.

The novel features of this invention, as well as the invention itself,will be best understood from the attached drawings, taken along with thefollowing description, in which similar reference characters refer tosimilar parts, and in which:

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

FIG. 1 is a diagram of the efferent autonomic nervous system;

FIG. 2 is a diagram of sympathetic nervous system anatomy;

FIG. 3 is an elevation view of the splanchnic nerves and celiac ganglia;

FIG. 4 is a schematic of an exemplary prior art stimulation patternwhich can be used in the method of the present invention;

FIG. 5 is a schematic of an exemplary prior art pulse generator whichcan be used in the method of the present invention;

FIG. 6 is a sketch of an exemplary prior art catheter-type lead andelectrode assembly which can be used in the method of the presentinvention;

FIG. 7 is a graph of known plasmal catecholamine levels in variousphysiologic and pathologic states;

FIGS. 8A, 8B, and 8C are exemplary graphs of the effect of splanchnicnerve stimulation on catecholamine release rates, epinephrine levels,and energy expenditure, respectively, which can be achieved in thepractice of the present invention;

FIG. 9 is a graph of known plasma ghrelin levels over a daily cycle, forvarious subjects; and

FIG. 10 is a section view of an exemplary instrument placement which canbe used in the method of the present invention, for implantation of anelectrode assembly.

DETAILED DESCRIPTION OF THE INVENTION

The human nervous system is a complex network of nerve cells, orneurons, found centrally in the brain and spinal cord and peripherallyin the various nerves of the body. Neurons have a cell body, dendritesand an axon. A nerve is a group of neurons that serve a particular partof the body. Nerves may contain several hundred neurons to severalhundred thousand neurons. Nerves often contain both afferent andefferent neurons. Afferent neurons carry signals back to the centralnervous system and efferent neurons carry signals to the periphery. Agroup of neuronal cell bodies in one location is known as a ganglion.Electrical signals are conducted via neurons and nerves. Neurons releaseneurotransmitters at synapses (connections) with other nerves to allowcontinuation and modulation of the electrical signal. In the periphery,synaptic transmission often occurs at ganglia.

The electrical signal of a neuron is known as an action potential.Action potentials are initiated when a voltage potential across the cellmembrane exceeds a certain threshold. This action potential is thenpropagated down the length of the neuron. The action potential of anerve is complex and represents the sum of action potentials of theindividual neurons in it.

Neurons can be myelinated and unmyelinated, of large axonal diameter andsmall axonal diameter. In general, the speed of action potentialconduction increases with myelination and with neuron axonal diameter.Accordingly, neurons are classified into type A, B and C neurons basedon myelination, axon diameter, and axon conduction velocity. In terms ofaxon diameter and conduction velocity, A is greater than B which isgreater than C.

The autonomic nervous system is a subsystem of the human nervous systemthat controls involuntary actions of the smooth muscles (blood vesselsand digestive system), the heart, and glands, as shown in FIG. 1. Theautonomic nervous system is divided into the sympathetic andparasympathetic systems. The sympathetic nervous system generallyprepares the body for action by increasing heart rate, increasing bloodpressure, and increasing metabolism. The parasympathetic system preparesthe body for rest by lowering heart rate, lowering blood pressure, andstimulating digestion.

The hypothalamus controls the sympathetic nervous system via descendingneurons in the ventral horn of the spinal cord, as shown in FIG. 2.These neurons synapse with preganglionic sympathetic neurons that exitthe spinal cord and form the white communicating ramus. Thepreganglionic neuron will either synapse in the paraspinous gangliachain or pass through these ganglia and synapse in a peripheral, orcollateral, ganglion such as the celiac or mesenteric. After synapsingin a particular ganglion, a postsynaptic neuron continues on toinnervate the organs of the body (heart, intestines, liver, pancreas,etc.) or to innervate the adipose tissue and glands of the periphery andskin. Preganglionic neurons of the sympathetic system are typicallymyelinated type B neurons and postganglionic neurons are typicallyunmyelinated type C neurons.

Several large sympathetic nerves and ganglia are formed by the neuronsof the sympathetic nervous system as shown in FIG. 3. The greatersplanchnic nerve (GSN) is formed by efferent sympathetic neurons exitingthe spinal cord from thoracic vertebral segment numbers 4 or 5 (T4 orT5) through thoracic vertebral segment numbers 9 or 10 or 11 (T9, T10,or T11). The lesser splanchnic (lesser SN) nerve is formed bypreganglionic fibers sympathetic efferent fibers from T10 to T12 and theleast splanchnic nerve (least SN) is formed by fibers from T12. The GSNis typically present bilaterally in animals, including humans, with theother splanchnic nerves having a more variable pattern, presentunilaterally or bilaterally and sometimes being absent. The splanchnicnerves run along the anterior-lateral aspect of the vertebral bodies andpass out of the thorax and enter the abdomen through the crus of thediaphragm. The nerves run in proximity to the azygous veins. Once in theabdomen, neurons of the GSN synapse with postganglionic neuronsprimarily in celiac ganglia. Some neurons of the GSN pass through theceliac ganglia and synapse on in the adrenal medulla. Neurons of thelesser SN and least SN synapse with post-ganglionic neurons in themesenteric ganglia.

Postganglionic neurons, arising from the celiac ganglia that synapsewith the GSN, innervate primarily the upper digestive system, includingthe stomach, pylorus, duodenum, pancreas, and liver. In addition, bloodvessels and adipose tissue of the abdomen are innervated by neuronsarising from the celiac ganglia/greater splanchnic nerve. Postganglionicneurons of the mesenteric ganglia, supplied by preganglionic neurons ofthe lesser and least splanchnic nerve, innervate primarily the lowerintestine, colon, rectum, kidneys, bladder, and sexual organs, and theblood vessels that supply these organs and tissues.

In the treatment of obesity, the preferred embodiment involveselectrical activation of the greater splanchnic nerve of the sympatheticnervous system. Preferably unilateral activation would be utilized,although bilateral activation could also be utilized. The celiac gangliacould also be activated, as well as the sympathetic chain or ventralspinal roots.

Electrical nerve modulation (nerve activation or inhibition) isaccomplished by applying an energy signal (pulse) at a certain frequencyto the neurons of a nerve (nerve stimulation). The energy pulse causesdepolarization of neurons within the nerve above the activationthreshold resulting in an action potential. The energy applied is afunction of the current amplitude and pulse width duration. Activationor inhibition can be a function of the frequency, with low frequencieson the order of 1 to 50 Hz resulting in activation and high frequenciesgreater than 100 Hz resulting in inhibition. Inhibition can also beaccomplished by continuous energy delivery resulting in sustaineddepolarization. Different neuronal types may respond to differentfrequencies and energies with activation or inhibition.

Each neuronal type (i.e., type A, B, or C neurons) has a characteristicpulse amplitude-duration profile (energy pulse signal) that leads toactivation. Myelinated neurons (types A and B) can be stimulated withrelatively low current amplitudes on the order of 0.1 to 5.0milliamperes and short pulse widths on the order of 50 to 200microseconds. Unmyelinated type C fibers typically require longer pulsewidths on the order of 300 to 1,000 microseconds and higher currentamplitudes. This difference in energy for activation can be utilized toselectively stimulate certain neurons in a nerve containing mixedneuronal types. This can be important in stimulating nerves such as thesplanchnic, because the splanchnic nerves contains both afferent painneurons, which are typically type C neurons, and efferent pre-ganglionicneurons, which are myelinated type B. If a therapy such as obesitytreatment involves splanchnic nerve activation, it would be desirable toactivate the efferent type B neurons and not the afferent type C painneurons. This may be accomplished by varying the energy pulse signal.

Two important parameters related to stimulation of peripheral nerves ofmixed neuronal type are the rheobase and chronaxie. These two parametersare a function of the stimulus duration and stimulus strength (currentamplitude). The rheobase is the lower limit of the stimulus strengthbelow which an action potential cannot be generated, regardless of thestimulus duration. The chronaxie is the stimulus duration correspondingto twice the rheobase. This is a measure of excitability of the mixedperipheral nerve. It is not desirable to stimulate a peripheral nerve atstimulus intensities greater than the chronaxie. The chronaxie of thesplanchnic nerve is likely between approximately 150 microseconds and400 microseconds.

Various stimulation patterns, ranging from continuous to intermittent,can be utilized. With intermittent stimulation, energy is delivered fora period of time at a certain frequency during the signal-on time asshown in FIG. 4. The signal-on time is followed by a period of time withno energy delivery, referred to as signal-off time.

Superimposed on the stimulation pattern are the treatment parameters,frequency and duration. The treatment frequency may be continuous ordelivered at various time periods within the day or week. The treatmentduration may last for as little as a few minutes to as long as severalhours. For example, splanchnic nerve activation to treat obesity may bedelivered at a frequency of three times daily, coinciding with mealtimes. Treatment duration with a specified stimulation pattern may lastfor one hour. Alternatively, treatment may be delivered at a higherfrequency, say every three hours, for shorter durations, say 30 minutes.The treatment duration and frequency can be tailored to achieve thedesired result.

Pulse generation for electrical nerve modulation is accomplished using apulse generator. Pulse generators can use conventional microprocessorsand other standard electrical components. A pulse generator for thisembodiment can generate a pulse, or energy signal, at frequenciesranging from approximately 0.5 Hz to 300 Hz, a pulse width fromapproximately 10 to 1,000 microseconds, and a constant current ofbetween approximately 0.1 milliamperes to 20 milliamperes. The pulsegenerator may be capable of producing a ramped, or sloped, rise in thecurrent amplitude. The preferred pulse generator can communicate with anexternal programmer and or monitor. Passwords, handshakes and paritychecks are employed for data integrity. The pulse generator can bebattery operated or operated by an external radiofrequency device.Because the pulse generator, associated components, and battery may beimplanted they are preferably encased in an epoxy-titanium shell.

A schematic of the implantable pulse generator (IPG) is shown in FIG. 5.Components are housed in the epoxy-titanium shell. The battery suppliespower to the logic and control unit. A voltage regulator controls thebattery output. The logic and control unit control the stimulus outputand allow for programming of the various parameters such as pulse width,amplitude, and frequency. In addition, the stimulation pattern andtreatment parameters can be programmed at the logic and control unit. Acrystal oscillator provides timing signals for the pulse and for thelogic and control unit. An antenna is used for receiving communicationsfrom an external programmer and for status checking the device. Theoutput section couples to the electrodes and leads that carry the energypulse to the nerve. The reed switch allows manual activation using anexternal magnet. Devices powered by an external radiofrequency devicewould limit the components to primarily a receiving coil or antenna.

The IPG is coupled to a lead and electrode assembly. The lead is abundle of electrically conducting wires insulated from the surroundingsby a non-electrically conducting coating. The wires of the lead connectthe IPG to the stimulation electrodes, which transfers the energy pulseto the nerve. A single wire may connect the IPG to the electrode, or awire bundle may connect the IPG to the electrode. Wire bundles may ormay not be braided. Wire bundles are preferred because they increasereliability and durability. Alternatively, a helical wire assembly couldbe utilized to improve durability with flexion and extension of thelead.

The electrodes are preferably platinum or platinum-iridium ribbons orrings as shown in FIG. 6. The electrodes are capable of electricallycoupling with the surrounding tissue and nerve. The electrodes mayencircle a catheter-like lead assembly. The distal electrode may form arounded cap at the end to create a bullet nose shape. Ideally, thiselectrode serves as the cathode. A lead of this type may contain 2 to 4ring electrodes spaced anywhere from 2.0 to 5.0 mm apart with each ringelectrode being approximately 1.0 to 10.0 mm in width. Catheter leadelectrode assemblies may have an outer diameter of 0.5 mm to 1.5 mm tofacilitate percutaneous placement using an introducer.

Bipolar stimulation of a nerve can be accomplished with multipleelectrode assemblies with one electrode serving as the positive node andthe other serving as a negative node. In this manner nerve activationcan be directed primarily in one direction (unilateral), such asefferently, or away from the central nervous system. Alternatively, anerve cuff electrode can be employed. Helical cuff electrodes asdescribed in U.S. Pat. No. 5,251,634 to Weinberg are preferred. Cuffassemblies can similarly have multiple electrodes and direct and causeunilateral nerve activation.

Unipolar stimulation can also be performed. As used herein, unipolarstimulation means using only a single electrode on the lead, while themetallic shell of the IPG, or another external portion of the IPG,essentially functions as a second electrode, remote from the firstelectrode. This type of unipolar stimulation may be more suitable forsplanchnic nerve stimulation than the bipolar stimulation method,particularly if the electrode is to be placed percutaneously underfluoroscopic visualization. With fluoroscopically observed percutaneousplacement, it may not always be possible to place the electrodesimmediately adjacent the nerve, which can be required for bipolarstimulation. With unipolar stimulation, a larger energy field is createdin order to electrically couple the electrode on the lead with theremote external portion of the IPG, and the generation of this largerenergy field can result in activation of the nerve even in the absenceof close proximity between the single lead electrode and the nerve. Thisallows successful nerve stimulation with the single electrode placedonly in “general proximity” to the nerve, meaning that there can besignificantly greater separation between the electrode and the nervethan the “close proximity” required for bipolar stimulation. Themagnitude of the allowable separation between the electrode and thenerve will necessarily depend upon the actual magnitude of the energyfield which the operator generates with the lead electrode in order tocouple with the remote electrode.

In multiple electrode lead assemblies, some of the electrodes may beused for sensing nerve activity. This sensed nerve activity could serveas a signal to commence stimulation therapy. For example, afferentaction potentials in the splanchnic nerve, created due to thecommencement of feeding, could be sensed and used to activate the IPG tobegin stimulation of the efferent neurons of the splanchnic nerve.Appropriate circuitry and logic for receiving and filtering the sensedsignal would be required in the IPG.

Because branches of the splanchnic nerve directly innervate the adrenalmedulla, electrical activation of the splanchnic nerve results in therelease of catecholamines (epinephrine and norepinephrine) into theblood stream. In addition, dopamine and cortisol, which also raiseenergy expenditure, can be released. Catecholamines can increase energyexpenditure by 15% to 20%. By comparison, subitramine, a pharmacologicagent used to treat obesity, increases energy expenditure by only 3% to5%.

Human resting venous blood levels of norepinephrine and epinephrine areapproximately 25 picograms (pg)/milliliter (ml) and 300 pg/ml,respectively, as shown in FIG. 7. Detectable physiologic changes such asincreased heart rate occur at norepinephrine levels of approximately1,500 pg/ml and epinephrine levels of approximately 50 pg/ml. Venousblood levels of norepinephrine can reach as high 2,000 pg/ml duringheavy exercise, and levels of epinephrine can reach as high as 400 to600 pg/ml during heavy exercise. Mild exercise produces norepinephrineand epinephrine levels of approximately 500 pg/ml and 100 pg/ml,respectively. It may be desirable to maintain catecholamine levelssomewhere between mild and heavy exercise during electrical sympatheticactivation treatment for obesity.

In anesthetized animals, electrical stimulation of the splanchnic nervehas shown to raise blood catecholamine levels in a frequency dependentmanner in the range of 1 Hz to 20 Hz, such that rates of catecholaminerelease/production of 0.3 to 4.0 μg/min can be achieved. These rates aresufficient to raise plasma concentrations of epinephrine to as high as400 to 600 pg/ml, which in turn can result in increased energyexpenditure ranging from 10% to 20% as shown in FIG. 8. Duringstimulation, the ratio of epinephrine to norepinephrine is 65% to 35%.It may be possible to change the ratio by stimulating at higherfrequencies. This may be desired to alter the energy expenditure and/orprevent a rise in MAP.

Energy expenditure in humans ranges from approximately 1.5 kcal/min to2.5 kcal/min. A 15% increase in this energy expenditure in a person witha 2.0 kcal/min energy expenditure would increase expenditure by 0.3kcal/min. Depending on treatment parameters, this could result in anadditional 100 to 250 kcal of daily expenditure and 36,000 to 91,000kcal of yearly expenditure. One pound of fat is approximately 3500 kcal,yielding an annual weight loss of 10 to 26 pounds.

Increased energy expenditure would need to be fueled by fat andcarbohydrate metabolism. Postganglionic branches of the splanchnic nerveinnervate the liver and fat deposits of the abdomen. Activation of thesplanchnic nerve can result in fat metabolism and the liberation offatty acids, as well as glycogen breakdown and the release of glucosefrom the liver. Fat metabolism coupled with increased energy expendituremay result in a net reduction in fat reserves.

It may also be desirable to titrate obesity therapy to plasma ghrelinlevels. In humans, venous blood ghrelin levels range from approximately250 pg/ml to greater than 700 pg/ml as shown in FIG. 9. Ghrelin levelsrise and fall during the day with peak levels typically occurring justbefore meals. In patients with gastric bypass surgery, an effectivetreatment for obesity, ghrelin levels are more static and typically stayin a low range of 100 to 200 pg/ml. Splanchnic nerve activation, in thetreatment of obesity, could be titrated to keep ghrelin levels in thelow range below 250 to 300 pg/ml. Reductions in food intake comparableto the increases in energy expenditure (i.e. 100 to 250 kcal/day), couldyield a total daily kcal reduction of 200 to 500 per day, and 20 to 50pounds of weight loss per year.

In anesthetized animals, electrical activation of the splanchnic nervehas also been shown to decrease insulin secretion. In obesity, insulinlevels are often elevated, and insulin resistant diabetes (Type II) iscommon. Down-regulation of insulin secretion by splanchnic nerveactivation may help correct insulin resistant diabetes.

Electrical activation of the splanchnic nerve can cause an increase inmean arterial blood pressure (MAP) above a baseline value. A drop in MAPbelow the baseline can follow this increase. Because a sustainedincrease in MAP is undesirable, the stimulation pattern can be designedto prevent an increase in MAP. One strategy would be to have arelatively short signal-on time followed by a signal-off time of anequal or longer period. This would allow the MAP to drop back to orbelow the baseline. The subsequent signal-on time would then raise theMAP, but it may start from a lower baseline. In this manner asinusoidal-like profile of the MAP could be set up during therapydelivery that would keep the average MAP within safe limits. The rise inMAP is accompanied by a decrease in heart rate which is a compensatorymechanism that may also normalize MAP with sustained stimulation formore than approximately 10 minutes.

Alternatively, an alpha-sympathetic receptor blocker, such a prazosincould be used to blunt the rise in MAP. Alpha-blockers are commonlyavailable antihypertensive medications. The rise in MAP seen withsplanchnic nerve stimulation is the result of alpha-receptor activation,which mediates arterial constriction. Because the affects of thistherapy on reduced food intake and energy expenditure are related tobeta-sympathetic receptor activity, addition of the alpha-blocker wouldnot likely alter the therapeutic weight loss benefits.

Implantation of the lead/electrode assembly for activation of thegreater splanchnic nerve is ideally accomplished percutaneously using anintroducer as shown in FIG. 10. The introducer could be a hollowneedle-like device that would be placed posteriorly through the skinbetween the ribs para-midline at the T9-T12 level of the thoracic spinalcolumn. A posterior placement with the patient prone is preferred toallow bilateral electrode placement at the splanchnic nerves, ifrequired. Placement of the needle could be guided using fluoroscopy,ultrasound, or CT scanning. Proximity to the splanchnic nerve by theintroducer could be sensed by providing energy pulses to the introducerto electrically activate the nerve while monitoring for a rise in MAP.All but the very tip of the introducer would be electrically isolated soas to focus the energy delivered to the tip of the introducer. The lowerthe current amplitude required to cause a rise in the MAP, the closerthe introducer tip would be to the nerve. Ideally, the introducer tipserves as the cathode for stimulation. Alternatively, a stimulationendoscope could be placed into the stomach of the patient for electricalstimulation of the stomach. The evoked potentials created in the stomachcould be sensed in the splanchnic nerve by the introducer. To avoiddamage to the spinal nerves, the introducer could sense evokedpotentials created by electrically activating peripheral sensory nerves.Once the introducer was in proximity to the nerve, a catheter type leadelectrode assembly would be inserted through the introducer and adjacentto the nerve. Stimulating the nerve and monitoring for a rise in MAPcould be used to confirm electrode placement. The lead and the IPG wouldbe implanted subcutaneously in the patient's back or side. The leadwould be appropriately secured to avoid dislodgement. The lesser andleast splanchnic nerves may also be activated to some degree bylead/electrode placement according to the above procedure, due to theirproximity to the splanchnic nerve.

Percutaneous placement of the lead electrode assembly could be enhancedusing direct or video assisted visualization. An optical port could beincorporated into the introducer. A separate channel would allow theelectrode lead assembly to be inserted and positioned, once the nervewas visualized. Alternatively, a percutaneous endoscope could beinserted into the chest cavity for viewing advancement of the introducerto the nerve. The parietal lung pleuron is relatively clear, and thenerves and introducer can be seen running along the vertebral bodies.With the patient prone, the lungs are pulled forward by gravity creatinga space for the endoscope and for viewing. This may avoid the need forsingle lung ventilation. If necessary, one lung could be collapsed toprovide space for viewing. This is a common and safe procedure performedusing a bifurcated endotracheal tube. The endoscope could also be placedlaterally, and positive CO₂ pressure could be used to push down thediaphragm, thereby creating a space for viewing and avoiding lungcollapse.

Alternatively, stimulation electrodes could be placed along thesympathetic chain ganglia from approximately vertebra T4 to T11. Thisimplantation could be accomplished in a similar percutaneous manner asabove. This would create a more general activation of the sympatheticnervous system, though it would include activation of the neurons thatcomprise the splanchnic nerves.

Alternatively, the lead/electrode assembly could be placedintra-abdominally on the portion of the splanchnic nerve that residesretroperitoneally on the abdominal aorta just prior to synapsing in theceliac ganglia. Access to the nerve in this region could be accomplishedlaparoscopically, using typical laparoscopic techniques, or via openlaparotomy. A cuff electrode could be used to encircle the nerveunilaterally or bilaterally. The lead could be anchored to the crus ofthe diaphragm. A cuff or patch electrode could also be attached to theceliac ganglia unilaterally or bilaterally. Similar activation of thesplanchnic branches of the sympathetic nervous system would occur asimplanting the lead electrode assembly in the thoracic region.

An alternative lead/electrode placement would be a transvascularapproach. Due to the proximity of the splanchnic nerves to the azygousveins shown in FIG. 10, and in particular the right splanchnic nerve andright azygous vein, modulation could be accomplished by positioning alead/electrode assembly in this vessel. Access to the venous system andazygous vein could occur via the subclavian vein using standardtechniques. The electrode/lead assembly could be mounted on a catheter.A guidewire could be used to position the catheter in the azygous vein.The lead/electrode assembly would include an expandable member, such asa stent. The electrodes would be attached to the stent, and usingballoon dilation of the expandable member, could be pressed against thevessel wall so that energy delivery could be transferred to the nerve.The expandable member would allow fixation of the electrode leadassembly in the vessel. The IPG and remaining lead outside of thevasculature would be implanted subcutaneously in a manner similar to aheart pacemaker.

While the particular invention as herein shown and disclosed in detailis fully capable of obtaining the objects and providing the advantageshereinbefore stated, it is to be understood that this disclosure ismerely illustrative of the presently preferred embodiments of theinvention and that no limitations are intended other than as describedin the appended claims.

1. A method for treating diabetes, comprising: monitoring a first patient parameter and a second patient parameter; and electrically activating a splanchnic nerve in said patient so as to achieve a desired change in said monitored parameter; wherein the splanchnic nerve is selected from the group consisting of the greater splanchnic nerve, the lesser splanchnic nerve, and the least splanchnic nerve; wherein said monitored parameter comprises an arterial blood pressure; and wherein said electrically activating comprises activating the sympathetic nervous system with stimulation parameters that keep the arterial blood pressure within safe limits.
 2. The method as recited in claim 1, wherein: said second parameter comprises an insulin level; and said electrically activating further comprises activating the splanchnic nerve to achieve a decreased insulin level.
 3. The method as recited in claim 2, wherein: said electrically activating has a signal-on no greater that a signal-off time.
 4. A method for treating Type II diabetes, comprising: monitoring a vital sign and a second parameter in a patient; and electrically activating the sympathetic nervous system of said patient so as to achieve a desired change in said second parameter; wherein said vital sign comprises an arterial blood pressure; said second parameter comprises an insulin level; and said electrically activating comprises activating the splanchnic nerve to achieve a decreased insulin level.
 5. The method as recited in claim 4, wherein: said electrical activation has a signal-on time no greater than a signal-off time. 